Yiqiang “Ken” Zhang, Ph.D.
Center for Cardiovascular Research
John A. Burns School of Medicine
651 Ilalo Street, BSB 311D
Honolulu, HI 96813
Phone: (808) 692-1480
The Translational Cardiobiology Laboratory focuses on major areas of disease-related research, including heart failure, diabetes, and arrhythmias. Dr. Zhang and his team study cardiac and stem cell biology, cell cycle control, epigenetics and functional genomics. Their programs focus on cardiac growth and disease mechanisms, heart failure, and regeneration therapies, diabetic cardiocomplications, and electrophysiology and arrhythmias. His team uses state-of-the-art transgenic and reporter cells and animal models bridging to human health. They use cutting-edge multi-omics and bioinformatics approaches, together with advanced cellular, molecular, and bioengineering technologies to tackle the challenging biomedical questions. By obtaining an in-depth understanding of mechanisms in cardiac development and disease processes, and endogenous and exogenous heart regeneration, and diabetic heart diseases, we hope to develop novel and effective therapeutics to treat congestive and congenital heart diseases.
Research in the Zhang lab includes the following themes: 1) Cardiomyocyte Growth, Dedifferentiation, and Cell Cycle Regulation. 2) Stem Cell and Cardiac Biology, Bioengineering, Cardiac Physiology, and Heart Regeneration. 3) Integrative Functional Multi-Omics in Heart Diseases. 4) Epigenetics of Diabetic Cardiocoplications. 5) Congenital Heart Diseases.
With the ultimate goal of treating degenerative heart diseases by promoting both endogenous and exogenous cardiac regeneration, the Zhang lab is working to determine the integrative cardiac and non-cardiac cellular processes and molecular pathways regulating cardiomyocyte differentiation, maturation, dedifferentiation, and cell cycle activities. His team uses state-of-the-art transgenic and reporter cells and animal models bridging to human health, cutting-edge multi-omics and bioinformatics approaches, together with advanced cellular, molecular, and bioengineering technologies.
1. Cardiomyocyte Growth, Dedifferentiation, and Cell Cycle Regulation
Based upon our early work on cardiomyocyte dedifferentiation, we have recently developed new multi-reporter transgenic mouse models for rigorous cardiomyocyte lineage tracing and real-time maturity (versus dedifferentiation) visualization (Figure 1). We continue studying molecular regulations of endogenous myocardial regeneration, namely cardiomyocyte dedifferentiation followed by proliferation, in injured (e.g., infarcted and hypertrophic) hearts. We use multi-disciplinary approaches, including high-throughput single-cell imaging, massive parallel single-nucleus RNA-seq and ATAC-seq, DNA methylome, and integrative cellular, molecular, and functional physiological analyses. We also use cell cycle-specific reporter systems and patient cardiac tissues to study heart cell hemostasis and mechanisms of endogenous myocyte renewal and regeneration.
2. Stem Cell and Cardiac Biology, Bioengineering, Cardiac Physiology, and Heart Regeneration
Pluripotent stem cells (e.g., induced pluripotent stem cells/iPSCs, or embryonic stem cells/ESCs) are the unique models used in cardiac development and heart regeneration research. We study cardiomyocyte differentiation, growth (maturation versus dedifferentiation), cell cycle (proliferation), cellular physiology, and how these processes are modulated by cellular cues such as bioengineered, nanopatterned surfaces (Figure 2), and their underlying molecular/epigenetic mechanisms. The overarching goals of our projects are to dissect molecular mechanisms regulating these multi-faceted processes in stem cells and heart cells and to generate important targets to enhance exogenous myocardial regeneration using cell therapies.
3. Integrative Functional Multi-Omnics in Heart Diseases
The Zhang laboratory is interested in applying large-scale multi-omic approaches to discover and translate knowledge for treating cardiovascular diseases (Figure 3). By taking advantage of novel transgenic models for cell lineage, cell cycle, and specific molecular expression, and using both animal models and human biopsies, we study the integrative transcriptomic and epigenomic regulations (e.g., chromatin accessibility by ATAC-seq, histone and DNA modifications, and miRNA) in cardiac development and disease remodeling. Our systematic investigations of global heart cell populations generate novel discoveries and comprehensive, in-depth knowledge critical in treating heart failure and other cardiac diseases.
View a complete list of Publications in MyBibliography:
Zhang Y‡, Gago-Lopez N, Li N, Zhang Z, Alver N, Liu Y, Martinson AM, Mehri A, MacLellan WR‡. Single-cell imaging and transcriptomic analyses of endogenous cardiomyocyte dedifferentiation and cycling. (Nature) Cell Discovery, 2019; 30; June 4, 2019; PMCID: PMC6547664. DOI : 10.1038/s41421-019-0095-9 (Corresponding author)
This is the first comprehensive work on cellular and molecular mechanisms of endogenous cardiomyocyte regeneration (via dedifferentiation, cell cycle-reentry, and proliferation) in novel triple-transgenic multi-reporter mice, analyzed with high-throughput single-cell imaging and massive parallel single-nucleus RNA-seq (snRNA-seq) technologies transformable to cardiovascular systems and broader biomedical sciences.
El-Nachef D, Oyama K, Wu YY, Liu Y, Zhang Y, MacLellan WR. Repressive histone methylation regulates cardiac myocyte cell cycle exit. J Mol Cell Cardiol. 2018; 121:1-12; PMID: 29800554 DOI: 10.1016/j.yjmcc.2018.05.013
Chen X*, Chakravarty T*, Zhang Y*, Li X, Zhong JF, Wang C. Single-cell transcriptome and epigenomic reprogramming of cardiomyocyte-derived cardiac progenitor cells. (Nature) Scientific Data. 2016; 3: 160079. PMID: 27622691 (*co-first author)
Zhang Y, Zhong JF, Qiu H, MacLellan WR, Marbán E, Wang C‡. Epigenomic reprogramming of adult cardiomyocyte-derived cardiac progenitor cells. (Nature) Sci. Rep. 2015; 5: 17686; doi: 10.1038/ srep17686. PubMed PMID: 26657817 (‡Co-Corresponding author)
Zhang Y, Mignone J, MacLellan WR, Cardiac Regeneration and Stem Cells. Physiol. Rev.2015; 95: 1189-204. PubMed PMID: 26269526
Gago-Lopez N, Awaji O, Zhang Y, Ko C, Nsair A, Liem D, Stempien-Otero A, MacLellan WR. THY-1 receptor expression differentiates cardiosphere-derived cells with divergent cardiogenic differentiation potential. Stem Cell Report, 2014;2:1-16. PMID: 24936447
Zhang Y, Matsushita N, Eigler T, Marbán. Targeted microRNA interference promotes postnatal cardiac cell cycle re-entry. J Regenerative Med. 2013;2:2. PMID: 24910852
Malliaras K, Zhang Y, Seinfeld J, Galang G, Tseliou E, Cheng K, Sun B, Aminzadeh M, Marbán E. Cardiomyocyte proliferation and progenitor cell recruitment underlie therapeutic regeneration after myocardial infarction in the adult mouse heart. EMBO Mol Med. 2013;5:191-209. PMID: 23255322
Li Z, Zhang C, Weiner LP, Chiou PY, Zhang Y, Zhong JF. Molecular characterization of heterogeneous mesenchymal stem cells with single-cell transcriptomes. Biotechnol. Adv. 2013;31(2):312-7. PMID: 23266308
Barth AS‡, Zhang Y, Li TS, Smith RR, Chimenti I, Terrovitis J, Davis D, Kizana E, Ho A, O’Rourke B, Wolff A, Gerstenblith G, Marban E. Functional impairment of human resident cardiac stem cells contributes to trastuzumab cardiotoxicity. Stem Cells Transl Med, 2012;1(4):289-97.. PMID: 23197808 (‡ equal first-author)
Li TS, Cheng K, Malliaras K, Matsushita N, Sun B, Marbán L, Zhang Y, Marbán E. Expansion of human cardiac stem cells in physiological oxygen improves cell production efficiency and potency for myocardial repair. Cardiovascular Res, 2011;89: 157-165. PMID: 20675298
Zhang Y, Li TS, Lee ST, Wawrowsky KA, Cheng K, Galang G, Malliaras K, Abraham RM, Wang C, Marbán E. Dedifferentiation and proliferation of mammalian cardiomyocytes. PLoS One 2010; 5: e12559. PMID: 20838637 (I.F. 4.537; 27,049 views)
The first study with genetic cell fate mapping and single-cell tracking techniques to demonstrate the substantial cellular plasticity of adult cardiomyocytes capable of dedifferentiation, cell cycle reactivation and proliferation.